Mental models or probabilistic reasoning or both: Reviewing the evidence for and implications of dual-strategy models of deductive reasoning

The present paper presents an overview of contemporary reasoning research to examine the evidence for and implications of the Dual Strategy Model of Reasoning. The Dual Strategy Model of Reasoning proposes that there are two types of reasoning strategy applied in deductive reasoning – counterexample and statistical. The paper considers Mental Models Theory and The Probability Heuristics Model as candidate specifications for these respective strategies and hypotheses are proposed on this basis. The Dual Strategy Model is further considered in the context of Dual Process theory, the Dual Source Model and Meta-reasoning and implications of the synergy between these proposals are considered. We finally consider the Dual Strategy Model in the context of individual differences, and normative considerations before proposing novel hypotheses and further avenues of research which we argue require exploration in this context.N/

A brief report on student gambling and how UK universities can support students

Purpose An estimated 1.2 million students gamble, equating to approximately two in every three students. In the UK, university students have reached the legal age to gamble; many have received significant sums of financial support and will be responsible for managing their own finances. Some UK universities have acknowledged that students engage in gambling activity and the need to provide gambling-related support. However, more research is needed to better understand student gambling activities and how universities can optimise provision of support. The purpose of this study was to enhance this understanding. Design/methodology/approach A total of 210 university students completed an online survey to provide details of their gambling behaviour and views on the types of support that they felt would best support students. Findings Both gambling and non-gambling students reported a preference for specialised gambling-related support within student services without the requirement for gambling-focused workshops (p < 0.01). Follow-up analysis revealed a significantly greater proportion of females did not gamble (p < 0.01), that males spent more money when gambling (p < 0.01) and were higher risk gamblers than females (p < 0.01). Originality/value These results provide evidence for gambling support to feature overtly as part of university support and well-being services

Development of the Critical Thinking Toolkit (CriTT): a measure of student attitudes and beliefs about critical thinking

Critical thinking is an important focus in higher education and is essential for good academic achievement. We report the development of a tool to measure critical thinking for three purposes: (i) to evaluate student perceptions and attitudes about critical thinking, (ii) to identify students in need of support to develop their critical thinking, and (iii) to predict academic performance. Seventy-seven items were generated from focus groups, interviews and the critical thinking literature. Data were collected from 133 psychology students. Factor Analysis revealed three latent factors based on a reduced set of 27 items. These factors were characterised as: Confidence in Critical Thinking; Valuing Critical Thinking; and Misconceptions. Reliability analysis demonstrated that the sub-scales were reliable. Convergent validity with measures of grade point average and argumentation skill was shown, with significant correlations between subscales and validation measures. Most notably, in multiple regression analysis, the three sub-scales from the new questionnaire substantially increased the variance in grade point average accounted for by measures of reflective thinking and argumentation. To sum, the resultant scale offers a measure that is simple to administer, can be used as a diagnostic tool to identify students who need support in developing their critical thinking skills, and can also predict academic performance

The Discovery of a Potent, Selective, and Peripherally Restricted Pan-Trk Inhibitor (PF-06273340) for the Treatment of Pain

The neurotrophin family of growth factors, comprised of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4), is implicated in the physiology of chronic pain. Given the clinical efficacy of anti-NGF monoclonal antibody (mAb) therapies, there is significant interest in the development of small molecule modulators of neurotrophin activity. Neurotrophins signal through the tropomyosin related kinase (Trk) family of tyrosine kinase receptors, hence Trk kinase inhibition represents a potentially “druggable” point of intervention. To deliver the safety profile required for chronic, nonlife threatening pain indications, highly kinase-selective Trk inhibitors with minimal brain availability are sought. Herein we describe how the use of SBDD, 2D QSAR models, and matched molecular pair data in compound design enabled the delivery of the highly potent, kinase-selective, and peripherally restricted clinical candidate PF-06273340

HBO1 is required for the maintenance of leukaemia stem cells.

Acute myeloid leukaemia (AML) is a heterogeneous disease characterized by transcriptional dysregulation that results in a block in differentiation and increased malignant self-renewal. Various epigenetic therapies aimed at reversing these hallmarks of AML have progressed into clinical trials, but most show only modest efficacy owing to an inability to effectively eradicate leukaemia stem cells (LSCs)1. Here, to specifically identify novel dependencies in LSCs, we screened a bespoke library of small hairpin RNAs that target chromatin regulators in a unique ex vivo mouse model of LSCs. We identify the MYST acetyltransferase HBO1 (also known as KAT7 or MYST2) and several known members of the HBO1 protein complex as critical regulators of LSC maintenance. Using CRISPR domain screening and quantitative mass spectrometry, we identified the histone acetyltransferase domain of HBO1 as being essential in the acetylation of histone H3 at K14. H3 acetylated at K14 (H3K14ac) facilitates the processivity of RNA polymerase II to maintain the high expression of key genes (including Hoxa9 and Hoxa10) that help to sustain the functional properties of LSCs. To leverage this dependency therapeutically, we developed a highly potent small-molecule inhibitor of HBO1 and demonstrate its mode of activity as a competitive analogue of acetyl-CoA. Inhibition of HBO1 phenocopied our genetic data and showed efficacy in a broad range of human cell lines and primary AML cells from patients. These biological, structural and chemical insights into a therapeutic target in AML will enable the clinical translation of these findings

Fragment screening for a protein-protein interaction inhibitor to WDR5

The WD40-repeat protein WDR5 scaffolds various epigenetic writers and is a critical component of the mammalian SET/MLL histone methyltransferase complex. Dysregulation of the MLL1 catalytic function is associated with mixed-lineage leukemia, and antagonism of the WDR5-MLL1 interaction by small molecules has been proposed as a therapeutic strategy for MLL-rearranged cancers. Small molecule binders of the “WIN” site of WDR5 that cause displacement from chromatin have been additionally implicated to be of broader use in cancer treatment. In this study, a fragment screen with Surface Plasmon Resonance (SPR) was used to identify a highly ligand-efficient imidazole-containing compound that is bound in the WIN site. The subsequent medicinal chemistry campaign—guided by a suite of high-resolution cocrystal structures with WDR5—progressed the initial hit to a low micromolar binder. One outcome from this study is a moiety that substitutes well for the side chain of arginine; a tripeptide containing one such substitution was resolved in a high resolution structure (1.5 Å) with a binding mode analogous to the native tripeptide. SPR furthermore indicates a similar residence time (kd = ∼0.06 s−1) for these two analogs. This novel scaffold therefore represents a possible means to overcome the potential permeability issues of WDR5 ligands that possess highly basic groups like guanidine. The series reported here furthers the understanding of the WDR5 WIN site and functions as a starting point for the development of more potent WDR5 inhibitors that may serve as cancer therapeutics

Small-Molecule Inhibition of PRMT5 Induces Translational Stress and p53 in JAK2V617F Mutant Myeloproliferative Neoplasms

Background: Myeloproliferative neoplasms (MPN) are a diverse group of hematopoietic stem cell disorders. JAK2V617F gain-of-function is the most prevalent mutation, accounting for more than 60% of MPNs. PRMT5 was initially identified as a JAK-binding protein. Its enzymatic function catalyses the symmetric di-methylation of arginine on a variety of substrates, including histones and proteins of the splicing apparatus. It has been proposed that mutant JAK2 can phosphorylate PRMT5, leading to loss of methylation activity and promotion of erythropoiesis (Liu F. et al. Cancer Cell 2011). Based upon this study, it was proposed that enhancing PRMT5 activity may be a useful therapeutic measure (Skoda RC et al. Cancer Cell 2011). Aim: To determine the role of PRMT5 in JAK2V671F mutant hematopoiesis. Hypothesis: Inhibition of PRMT5 will exacerbate JAK2V617F hematopoiesis Results: Using a conditional null allele, we deleted Prmt5 in embryonic development with the hematopoietic-specific VavCre transgene. This led to embryonic lethality at E9.5 due to absence of erythropoiesis but not other lineages. Similar embryonic lethality was observed using the erythroid specific EpoRCre transgene

Subtype-selective small molecule inhibitors reveal a fundamental role for Nav1.7 in nociceptor electrogenesis, axonal conduction and presynaptic release

Human genetic studies show that the voltage gated sodium channel 1.7 (Nav1.7) is a key molecular determinant of pain sensation. However, defining the Nav1.7 contribution to nociceptive signalling has been hampered by a lack of selective inhibitors. Here we report two potent and selective arylsulfonamide Nav1.7 inhibitors; PF-05198007 and PF-05089771, which we have used to directly interrogate Nav1.7's role in nociceptor physiology. We report that Nav1.7 is the predominant functional TTX-sensitive Nav in mouse and human nociceptors and contributes to the initiation and the upstroke phase of the nociceptor action potential. Moreover, we confirm a role for Nav1.7 in influencing synaptic transmission in the dorsal horn of the spinal cord as well as peripheral neuropeptide release in the skin. These findings demonstrate multiple contributions of Nav1.7 to nociceptor signalling and shed new light on the relative functional contribution of this channel to peripheral and central noxious signal transmission